We have pursued studies involving the properties and function of VIP (vasoactive intestinal peptide) and related peptides in three areas. We have examined the role of VIP as a peptidergic neurotransmitter using isolated gastric smooth muscle cells. VIP relaxed CCK-contracted smooth muscle cells in a dose-dependent manner. The kinetics of the process were rapid (5-30 sec). Addition of a phosphodiesterase inhibitor potentiated the action of VIP and increased the intracellular levels of cAMP. The studies demonstrated the existence of VIP receptors on smooth muscle cells which mediate cAMP-dependent relaxation. The effect of opioid peptides (met- and leu-enkephalin) was contractile in a dose-dependent manner and specifically blocked by naloxone. The effects of VIP and opioid peptides are consistent with the view that neurally located peptides act as peptidergic neurotransmitters in the gut. These studies are being expanded to peptides structurally related to VIP to determine the intracellular mode of action. A second area of research involved studies of the origin of circulating VIP in the dog. Oxytocin and neostigmine were found to be potent releasers of VIP from the gut. Their effects were blocked by cholinergic antagonists and neurotoxins consistent with release of VIP from intrinsic neurons of the gut under preganglionic cholinergic control. These studies are being pursued in an in vitro vascularly perfused intentinal preparation. The secretion of antral peptides was also studied in a vascularly perfused rat preparation. Cholinergic agents were shown to be stimulants of gastrin and inhibitors of somatostatin secretion. The reciprocity of the two peptides suggested a functional linkage between them. This was confirmed by the infusion of somatostatin antiserum which reversibly stimulated gastrin secretion. These studies are being pursued to determine the functional linkage of other peptides, chiefly bombesin and antral VIP, to gastrin secretion.